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ABSTRACT Durlobactam, a diazabicyclooctane β-lactamase inhibitor, exhibits direct antibacterial activity by binding to penicillin-binding protein 2 (PBP2). We generated a mutant strain of New Delhi metallo-β-lactamase-producing Escherichia coli with a durlobactam minimum inhibitory concentration of 2 µg/mL, representing a 16-fold increase from baseline, by exposing it to increasing concentrations of durlobactam. Resistance was attributed to a point mutation in the mrdA gene, resulting in a V522I substitution in PBP2.

Abstract Patients with hematologic diseases have experienced COVID-19 with prolonged, progressive course. Here we present clinical, pathological, and virological analyses of three cases of prolonged COVID-19 among patients undergoing treatment for B-cell lymphoma. These patients had all been treated with anti-CD20 antibody and bendamustine. Despite various antiviral treatments, high SARS-CoV-2 levels persisted for more than 4 weeks, and two of them succumbed to COVID-19. Autopsy showed bronchopneumonia, interstitial pneumonia, alveolar hemorrhage, and fibrosis. Overlapping CMV, fungal and/or bacterial infections were also confirmed. Sequencing of SARS-CoV-2 showed accumulation of mutations and changes in variant allele frequencies over time. NSP12 mutations V792I and M794I appeared independently in two cases as COVID-19 progressed. In vitro drug susceptibility analysis and animal experiment using recombinant SARS-CoV-2 demonstrated that each mutation, V792 and M794I, was independently responsible for remdesivir resistance and attenuated pathogenicity. E340A, E340D and F342INS mutations in the spike protein were found in one case, which may account for the sotrovimab resistance. Analysis of autopsy specimens indicated heterogeneous distribution of these mutations. In summary, we demonstrated temporal and spatial diversity in SARS-CoV-2 that evolved resistance to various antiviral agents in malignant lymphoma patients under immunodeficient conditions caused by certain types of immunochemotherapies. Strategies may be necessary to prevent acquisition of drug resistance and improve outcome, such as selection of appropriate treatment strategies for lymphoma considering patients’ immune status and institution of early intensive antiviral therapy.